5beta,6beta-methylene steroids



eve a t ABSTRACT OF THE DISCLOSURE Novel 5,3,6/3-methylene steroids of the 19-norpregnene and 19-norandrostene series prepared by the reaction of l9-hydroxy-A steroids with an u-fluorinated amine which are useful therapeutic agents.

This is a continuation-in-part of US. application Ser. No. 538,431, filed Mar. 29, 1966, now abandoned.

The present invention relates to novel cyclopentanophenanthrene derivatives and to processes for their preparation. More particularly, this invention relates to 53,6,8- methylene-l9-norpregn-9-ene and 5fi,6,8-methylene-l9-nor pregn-l 10) -ene derivatives.

The compounds of the present invention may be represented by the formula:

wherein R is an oxygen atom or the group OR I.......R or

in which R is hydrogen, hydroxy or acyloxy, R is hydrogen, tetrahydropyranyl or acyl, and R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl; and Z is a double bond between C1 and C-10 or between C-9 and C-10.

The hydrocarbon carboxylic acyl and acyloxy groups of the compounds of the present invention will contain less than 12 carbon atoms and may be of a straight, branched, cyclic or cyclic-aliphatic chain structure. This structure may be saturated, unsaturated or aromatic, and optionally substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like. Typical esters thus include acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, fi-chloropriopionate, adamantoate, and the like.

Those compounds having the 2-carbon pregnane side chain in the Hit-position and those having a 17a-alkynyl substituent demonstrate progestational activity and are useful in the control of fertility and in the treatment of various menstrual disorders. Those compounds of the present invention having a divalent oxygen atom in the 17- position and those having a l7fl-hydroxy group with or without alkyl or alkenyl substitution in the Nix-position are anabolic agents useful in the treatment of debilitory conditions such as old age, postoperative recuperation, and

the like. The compounds of the present invention also exhibit anti-androgen properties and are thus valuable in the treatment of acne, benign prostate hypertrophy and hirsutism in females.

The compounds of the present invention may be prepared via utilization of the following reaction:

AcO I III In the foregoing, Ac is acyl and R is an oxygen atom or the group l CH2 AcO in which X is fluoro or chloro; X is fluoro, chloro or trifluoromethyl; each of A and B are alkyl of 1 to 6 carbon atoms or, taken together, alkylene of from 5 to 7 carbon atoms inclusively. Typical of such reactants are l-diethylamino 1,1,2 trifluoro-Z-chloroethane, l-dimethylaminol,1,2,2-tetrafiuoroethane, l-dipropylamino-1,1,2-trifluoro- 2 chloroethane, l-diethylamino-1,1-difiuoro-2,2-dichloroethane, and the like. The reaction is generally conducted at elevated temperatures in an inert, nonpolar, organic solvent such as methylene chloride, dihydrofuran or acetonitrile. One convenient method utilizes the reflux temperature of the solvent, e.g. acetonitrile, to control the reaction temperature.

Upon such treatment with a slight excess, e.g. 1.5 molar equivalents, of the above a-fluorinated amine for a period of time of from about one to about two hours, there is obtained a mixture of the acyloXy-5,B,6B-methylene-A and 3 fi-acyloxy-S {3,6fl-methylene-A -steroids of Formula III. These two components may be separated via conventional techniques such as fractional crystallization, chromatography, or the like, or the mixture may be further processed with separation being effected at a later stage of the reaction sequence if desired.

In the case of the 5,8,6/3-methylene-19-norpregn-9-enes and -19-norpregn-1 (10)-enes of Formula III, conventional saponification, as with potassium bicarbonate or potassium hydroxide in methanol, then yields the corresponding hydroxy derivatives, which may be oxidized as with chromic acid to yield the Sofie-methylene-l9-norpregn-9- ene-3,20-diones and Sofie-methylene-19-norpregn-1(10)- ene-3,2()-diones. The 17x-acyloxy group, when present in these derivatives, may be hydrolyzed via conventional techniques, as with refluxing methanolic potassium bicarbonate, and the resulting 17a-hydr0xy compound may in turn be reacylated, if desired, with a carboxylic acid anhydride in the presence of an acid catalyst such as ptoluenesulfonic acid.

In the case of the 3,8-acyloxy-5p,6,8-methyleneestr-9- ones and 3fl-acyloxy-5fi,6fi-methyleneestr-1(l0)-enes of Formula HI, the l7-keto derivatives may be subjected to the analogous synthetic routes described above to yield the corresponding 55,6p-methyleneestr-9-ene-3,17-dione and -ester-1(10)-ene-3,17-dione, or alternatively may be treated with a lower alkyl, lower alkenyl or lower alkynyl magnesium halide, or with an alkyl lithium salt, or with an alkenyl sodium or potassium salt to yield the corresponding 56,6,8-methylene 17B hydroxyester-Q-ene or -estr-l (l)-ene substituted in the 170t-pOSlilOI1 by a lower alkyl, lower alkenyl or lower alkynyl group. Such 17cclower alkynyl derivatives may in turn be converted to the corresponding l7cc-1OW6I alkenyl or 17zx-1DW61' allcyl derivative via conventional controlled catalytic hydrogenation. These derivatives may then be hydrolyzed, if such has not already been done, and oxidized as previously described to yield the corresponding 3-keto-5f3,6;9-methylene-l7 3-hydroxyestr-9-ene or -estr-1(l0)-ene substituted in the l7a-position by a lower alkyl, lower alkenyl or lower alkynyl group. The tertiary 17fl-hydroxy group may be acylated via conventional techniques, as for example with acetic anhydride and p-toluenesulfonic acid in benzene.

In the case of the 5,8,6/3-methylene-17B-hydroxyestr-9- ene or -estr-1(10)-ene bearing only a hydrogen atom in the Nix-position, the corresponding 3,17-dione is first reduced with a metal hydride such as lithium aluminum hydride, and the resulting 3,17-dio1 is then back oxidized as with 2,3-dichloro-5,6-dicyanobenzoquinone to yield the desired 3-keto-17fl-hydroxy compound. This l7j8-hydroxy derivative may be acylated via conventional techniques, as for example with acetic anhydride in pyridine, to yield the corresponding 17f3-acylates.

Formation of the l7fi-tetrahydropyranyl ethers may be obtained via treatment of the corresponding Uri-hydroxy compound with dihydropyran in the presence of an acid catalyst.

The 5,8,65-methylene-A derivatives of the present invention may be further modified to the corresponding A derivatives through treatment with acid or base, preferably with a dilute solution of sodium methoxide in methanol. Thus provided are compounds having analogous utilities to those described above and having the formula:

wherein R is as defined above.

The following examples will serve to further typify t the nature of this invention, but being presented solely for the purpose of illustration, they should not be construed as a limitation thereof.

Example 1 A solution of 11.2 g. of 3B-acetoxy-Ztl-ketopregn-S-en- 19-01 in 125 ml. of anhydrous acetonitrile is refluxed for one hour under anhydrous conditions with 8.5 g. of ldiethylamino-l,1,2-trifluoro-2-chloroethane. The total reaction product is chromatographed on 600 g. of alumina, eluting the column first with hexane and then with methylene chloride. The crystalline fractions are combined and recrystallized from methanol, thus yielding 5.7 g. of 35 acetoxy S t-3,6,8 methylene 19 norpregn 1(10)- en-20one, melting point l04l05 C.; [Ct] +77 (CHCl The mother liquors and oily fractions are rechromatographed on 300 g. of alumina, eluting with 4:1 hexane: ether to yield 2 g. of 3B-acetoxy-55,6,6 -methylene-19- norpregn-9-en-20-one, melting point 7678 C.;

(CHCl )t max. 217-218 mm, log 5 3.89.

In a similar fashion, 3,8,17or-diacetoxy-5,6,6,B-methylene-l9-norpregn-1(10)-en-20-one and 3,6,17a-diacetoxy- 5,8,65-methylene-19-norpregn-9-en-20-one are prepared from 35,17ot-diacetoxy-ZO-ketopregn-S-en-19-01.

Example 2 One gram of 3 3-acetoxy-5p,6B-methy1ene-l9-norpregn- 1(l0)-en-20-One is allowed to stand at room temperature for 15 hours with 1 g. of potassium bicarbonate in 10 ml. of water and ml. of methanol. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields BB-hydroxy-SB,6B-methylene-19-norpregnl(10)-en-20-one, which is collected by filtration and re crystallized from acetone: hexane.

In a similar fashion, the following compounds are prepared: 3 ,8-hydroxy-53,6,8-methylene-l9-norpregn-9-en-20- one; 3/3 hydroxy 55,6,8-methylene-17a-acetoxy-l9-norpregn-1(10)-en-20-one and 3,13-hydroxy-5t3,Gfl-methylenel7rx-acetoxy-19-norpregn-9-en-20-one.

Example 3 To a solution of 9 g. of sodium dichromate in 6 ml. of sulfuric acid and ml. of water cooled to 5 C., there is added a solution of 2 g. of 3p-hydroxy-5fi,6fi-methylene-19-norpregn-1(lO)-en-20-one in 800 ml. of ether, the reaction mixture being stirred at the same temperature for one and one-half hours. The organic layer is separated and washed with sodium bicarbonate solution and water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is recrystallized from acetonezhexane, thus yielding 55,65- methylene-l9-norpregn 1(10) ene-3,20-dione, melting point 117-118 C.; [a] 129 (CHCl Likewise, the following compounds are prepared via the procedure of this example: 55,6;i-methylene-19-norpregn-9-ene-3,20-dione; 5,8,613-methylene-17a-acetoxy-19- norpregn 1(10) ene-3,20-dione; and 51?,6fi-methylene- Not-acetoxy-19-norpregn 9-ene-3,20-dione.

Example 4 A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5 m1. of methanol is added over a period of 30 minutes to a refluxing solution of 1 g. of 5 9,65- methylene 17a acetoxy 19 norpregn 9 ene 3,20- dione in 30 ml. of methanol under nitrogen. The solution is refluxed for two hours, cooled, neutralized with acetic acid and concentrated under reduced pressure. After the addition of water, the solid which forms is collected by filtration and dried to yield 55,6/3-methylene- 17u-hydroxy-19-norpregn-9-ene-3,20-dione, which is recrystallized from acetonezhexane.

513,65 methylene a hydroxy 19 norpregn- 1(10)-ene-3,20-dione is prepared in a similar fashion from the corresponding I'M-acetoxy derivative.

Example 5 To a solution of 5 g. of 55,6/3-methylene-Nix-hydroxy- 19-norpregn-9-ene-3,20-dione in 100 ml. of anhydrous benzene are added 1 g. of p-toluenesulfonic acid and 10 ml. of propionic anhydride. The mixture is allowed to stand for 24 hours at room temperature and is then poured with stirring into ice and water. The-organic phase is separated, washed with 10% sodium carbonate solution and with water, dried and evaporated to yield 55,65 methylene 17a propionoyloxy 19 norpregn- 9-ene-3,20-dione, which is further purified through recrystallization from ether2hexane.

53,613 methylene 17oz propionoyloxy l9 norpregn-l(10)-ene-3,20-dione is obtained in a similar fashion from the corresponding Nor-hydroxy compound.

By utilizing other anhydrides, such as caproic anhydride, in the foregoing procedure, the analogous 17aacylates are obtained, e.g. 5ti,6B-methylene-17rx-caproyl oxy-l9-norpregn-1(10)-ene-3,20-dione and 513,6;8-methylene-17a-caproyloxy-19-norpregn-9-ene-3,20-dione.

Example 6 A mixture of 5.54 g. of 35-acetoxy-l9-hydroxyandrost- 5-en-17-0ne and 4.56 g. of l-diethylamino-l,1,2-trifiuoro- 2-chloroethane in 100 ml. of anhydrous acetonitrile is heated at reflux temperatures for one hour. At the end of this time, the mixture is allowed to reach room temperature and is then chromatographed on 300 g. of alumina, eluting with hexane, to yield 35-acetoxy-55,65 methyleneestr-9-en-l7-one and 35-acetoxy-55,65-methyleneestr-l -en-17-0ne.

A mixture of 1 g. of 35-acetoxy-55,65-methyleneestr-9- en-17-one and ml. of a 2% methanolic potassium hydroxide solution is heated at steam bath temperatures until solution is complete. This solution is allowed to stand at room temperature for about 15 hours and is then diluted with water. The solid thus formed is collected by filtration, washed with water to neutrality and dried in vacuo to yield -hydroxy-55,65-methyleneestr-9-en-17- one, melting point 158-160 C., which is recrystallized from acetone.

To a solution of 4.0 g. of 35-hydroxy-55,65 methyleneestr-9-en-l7-one in 100 ml. of acetone are added, while stirring at a temperature of from 0-5 C., 5 ml. of an 8 N solution of chromic acid. After five minutes, the mixture is diluted wit-h water and extracted with ether. These extracts are washed with an aqueous sodium bicarbonate solution and water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 55,65-methyleneestr-9-ene-3,l7-dione, belting point 149150 C.

In a similar fashion, 35-acetoxy-55,65-methyleneestr- 1(10)-en-17-one is converted to the corresponding 35- hydroxy compound, which when oxidized as described above yields 55,65-methyleneester-1(10)-ene-3,l7-dione.

Example 7 A solution of 5 g. of 35-acetoxy-55,65-methyleneestr- 9-en-l7-one in 250 ml. of thiophene-free benzene is treated with 27.5 ml. of 4 N methylmagnesium bromide in anhydrous ether. The mixture is heated at reflux under anhydrous conditions for three hours, cooled, and cantiously treated with an excess aqueous ammonium chloride solution. This mixture is then extracted with ethyl acetate and these extracts are in turn washed with water, dried over sodium sulfate and evaporated to dryness to yield 55,65-methylene-17a-methylestr-9-ene-35,l75-diol, which is recrystallized from methylene chloride:hexane. By subjecting this compound to the oxidation procedure described in Example 6, there is obtained 55,65-methylene-17a-methylestr-9-en-175-ol-3-one.

In a similar fashion, by utilizing ethyl-, vinyl-, and prop1-enylmagnesium bromide in the foregoing procedure there are respectively obtained: 55,65-methylenel7a-ethylestr-9-en-175-ol-3-one; 55,65-methylene-17u-vinylestr-9-en-175-ol-3-one; and 55,65-methylene-17oc-pr0pl-enyl)-estr-9-en-l75-ol-3-one.

By utilizing 3 5-acetoxy-55,65-methylene-estr-1(10)-en- 17-one as the starting material in the above'procedure, there are respectively obtained: 55,65-methylene-17amethylestr-l 10 -en-l75-ol-3-one; 55,65-methylene-17a ethylestr-l l0)-en-l75-ol-3-one; 55,65-methylene-17a-vinylester-l(l0)-en-l75-ol-3-one; and 55,65-methylene-17a- (prop-l-enyl)-estr-l (l0)-en-175-ol-3-one.

Example 8 A solution of l g. of 35- acetoxy-55,65-methyleneestr- 9-en-l7-one in 30 ml. of anhydrous benzene is added under nitrogen to a solution of 1.4 g. of potassium in 30 ml. of t-amyl alcohol. A slow current of purified acetylene is then passed through the solution for hours. The mixture is diluted with water and extracted with benzene. These extracts are washed with water to neutrality, dried over sodium sulfate and evaporated. Chromatography of the residue on alkaline alumina with 2:3 hexanezbenzene yields 55,65-methylene-17a-ethynylestr-9-ene-35,175-diol, which is recrystallized from acetone:hexane. Upon subjecting this compound to the oxidation procedure of Example 6, there is obtained 55,65-methylene-17a-ethynylestr-9-en-175-ol-3-0ne.

In a similar fashion there is obtained 55,65-methylene- 17a-ethyny1estr-l'(10)-en-175-0l-3-one fromthe corresponding estr-1(10)-ene.

Example 9 To a solution of 5 g. of 55,65-methylene-l7a-ethynylestr-9-en-175-ol-3-one in ml. of anhydrous benzene are added 1 g. of p-toluenesulfonic acid and 10 ml. of acetic anhydride. The mixture is allowed to stand for 24 hours at room tempearture and is then poured with stirring into ice and water. The organic phase is separated, washed with 10% sodium carbonate solution and with water, dried and evaporated to yield 55,65-methylene- 17a-ethynyl-175-acetoxyestr-9-en-3-one, which is further purified through recrystallization from ether:hexane.

In a similar fashon there is obtained 55,65-methylene- 17a-ethynyl-175-acetoxyestr-1(10)-en-3-one from the corresponding l75-hydroxy compound.

By substituting propionic, caproic, cyclopentylpropionic,, enanthic and the like anhydrides, in place of acetic anhydride, the corresponding 175-acyloxy derivatives are obtained. Likewise, the other Una-substituted estr-9-enes and estr-1(10)-enes of the present invention are similarly esterified via the foregoing procedure. Typical of such derivatives are the following: 55,65-methylene-l7a-methyl-175-acetoxyestr-9-en-3-one; 55,65-methylene-17u-methyl-l75-propion0yloxyestr-9-en-3-one; 5 5,65 methylene- 17u-(prop-1-enyl)-l75-caproyloxyestr-9-en-3-one; 55,65- methylene-l7a-vinyl-l75-acetoxyestr-9-en 3 one; 55,65- methylene 17oz methyl 175 propionoyloxyestr- 1(10)-en-3-one; 55,65-17wethynyl-l75-cyclopentylpropionoyloxyestr-l 10 -en-3-one; and 5 5,65-methylene-l7avinyl- 17 5-enanthoyloxyestr-1 10') -en-3 one.

Example 10 Two milliliters of dihydropyran are added to a solution of l g. of 55,65-methylene-17a-methylestr-9-en-175-01-3- one in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for four days and is then washed with an aqueous sodium carbonate solution and water, dried and evaporated. This residue is chromatographed on neutral alumina, eluting with hexane, to yield 5 5,65-methylene- 17 a-methyl- 17 5-tetrahydropyranyloxyester-9-en-3-one, which is recrystallized from pentane.

In a similar fashion, the following compounds of the present invention are prepared: 55,65-methylene-17uethyl 175 tetrahydropyranyloxyestr 9 en 3 -one; 5 5,65 methylene a vinyl tetrahydropyranyloxyestr 9 en 3 one; 55,65 methylene 171x (prop- 1 enyl) 175 tetrahydropyranyloxyestr 9 en 3 one; 55,65 methylene 17a ethynyl 175 tetrahydropyranyloxyester 9 en 3 one; 55,65 methylene 17amethyl 175 tetrahydropyranyloxyestr 1(10) en 3 one; 55,65 methylene 17cc ethyl 175 tetrahydropyranyloxyestr 1(10) en 3 one; 55,65 methylene 17m vinyl 175 tetrahydropyranyloxyestr 1(10) en- 3 one; 55,65 methylene 17cc (prop 1- enyl) 175 tetrahydropyranyloxyestr 1(10) en 3 one; and 55,65- methylene 17a ethynyl 175 tetrahydropyranyloxyestr-1(10) -en-3 one.

What is claimed is:

1. A process for the preparation of a 35 acyloxy 55,65 methylene 19 nor steroid which comprises treating a 35 acyloxy 19 hydroxy A steroid with an a-fiuorinated amine of the formula:

wherein,

X is fiuoro or chloro;

X is fluoro, chloro or trifiuoromethyl; and

each of A and B is lower alkyl of one to six carbon atoms, or taken together, alkylene of five to seven carbon atoms, said treatment being conducted at elevated temperatures in an inert nonpolar solvent.

2. The process of claim 1 wherein the a-fiuorinated amine is 1 diethylamino 1,1,2 trifluoro 1 chloroethane, the inert nonpolar solvent is acetonitrile, and the treatment is conducted at reflux temperatures.

3. The process of claim 2 wherein the starting material is a 3,8 acetoxy l9 hydroxypregn en 20 one having either hydrogen or an acyloxy group in the 17:1- position.

4. The process of claim 3 wherein the starting material is 3B,l7oz diacetoxy 19 hydroxypregn 5 en 20' one.

5. The process of claim 2 wherein the starting material is 35 acetoxy l9 hydroxyandrost 5 en 17 one.

6. A compound selected from those of the formula:

wherein,

R is an oxygen atom, the group or the group in which R is hydrogen, hydroxy or a hydrocarbon acyloxy group of less than 12 carbon atoms; R is hydrogen, tetrahydropyranyl or a hydrocarbon acyl group of less than 12 carbon atoms; R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl; and Z is a double bond between C-1 and C- or between (3-9 and C-10. 7. A compound according to claim 6 wherein R is an oxygen atom.

8. A compound according to claim 6 wherein Z is a double bond between C-9 and C40.

9. A compound according to claim 6 wherein R is the' group in which R is as defined therein.

10. A compound according to claim 9 wherein R is hydrogen.

11. A compound according to claim 9 wherein Z is a double bond between C-1 and C-10.

12. A compound according to claim 9 wherein R is acyloxy and Z is a double bond between C-9 and C-10.

13. A compound according to claim 9 wherein R is acetoxy.

14. Compounds according to claim 9 wherein R is acyloxy and Z is a double bond between C-1 and C-10. 15. A compound according to claim 9 wherein R is hydroxy.

16. A compound according to claim 6 wherein R is the group in which R and R are as defined therein.

17. A compound according to claim 16 wherein R and R are hydrogen.

18. A compound according to claim 16 wherein Z is a double bond between C9 and C-lO.

19. A compound according to claim 16 wherein R is hydrogen, or acetyl, R is methyl and Z is a double bond between C-1 and C-10.

20. A compound according to claim 16 wherein R is hydrogen or acetyl, R is methyl and Z is a double bond between C9 and C10.

21. A compound according to claim 16 wherein R is hydrogen or acetyl, R is ethyl and Z is a double bond between C-1 and C-1 0.

22. A compound according to claim 16 wherein R is hydrogen or acetyl, R is ethyl and Z is a double bond between C9 and C10.

23. A compound according to claim 16 wherein R is hydrogen or acetyl, R is vinyl and Z is a double bond between C-1 and C-lO.

24. A compound according to claim 16 wherein R is hydrogen or acetyl, R is vinyl and Z is a double bond between C9 and 0-10.

25. A compound according to claim 16 wherein R is hydrogen or acetyl, R is ethynyl and Z is a double bond between C1 and (3-10.

26. A compound according to claim 16 wherein R is hydrogen or acetyl, R is ethynyl and Z is a double bond between C-9 and Cl0.

References Cited UNITED STATES PATENTS 3,277,125 10/1966 Tadanier.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 

